Search Results (31)

Ovarian cancer is the most lethal gynecological cancer. Up to 75% of cases are high-grade serous ovarian cancer (HGSOC) that have high chemosensitivity to first-line platinum-based therapies. However, 75% of patients will become chemoresistant following relapse. The underlying mechanism for developing resistance to chemotherapy in HGSOC is poorly understood. In this study, we employed Matrix-Assisted Laser Desorption/Ionization–Mass Spectrometry Imaging (MALDI-MSI) on matching formalin-fixed paraffin-embedded (FFPE) HGSOC tissues at the time of diagnosis and following relapse with chemotherapy-resistant disease (n = 4). We identified m/z values that were differentially abundant in the matching diagnosis and relapse HGSOC tissues. These were matched to proteins using nano-liquid chromatography tandem mass spectrometry (LC-MS/MS). We identified upregulated proteins in the HGSOC relapse tissues, including COL12A1, FUBP1, PLEC, SLC4A1, and TKT. These proteins were validated by immunohistochemistry (IHC) and gene expression using online databases. IHC showed COL12A1, FUBP1, PLEC, SLC4A1, and TKT protein abundance were significantly elevated in HGSOC relapse tissues compared to matching tissues at diagnosis. COL12A1, FUBP1, PLEC, and TKT mRNA expression levels were significantly increased in HGSOC compared to normal ovary and associated with poor prognosis in HGSOC. We confirmed that higher protein abundance of both COL12A1 and PLEC correlated with reduced progression-free survival in HGSOC patients. Furthermore, both COL12A1 and PLEC mRNA and protein levels were significantly associated with chemotherapy resistance. In summary, using MALDI-MSI, we have identified proteins, including COL12A1 and PLEC, associated with chemotherapy resistance to be further evaluated as HGSOC biomarkers and/or therapeutic targets. Full article

Adipose tissue metabolism plays a crucial role in sheep meat quality and the optimization of adipose tissue utilization. To reveal the molecular mechanisms of adipose tissue metabolism during growth in naturally grazing sheep, we investigated the mRNA and miRNA profiles in subcutaneous adipose tissue (SAT) from naturally grazing Sunit sheep at 6, 18, and 30 months of age (Mth-6, Mth-18, and Mth-30). We identified 927 differentially expressed (DE) genes and 134 DE miRNAs in the SAT of sheep at different growth stages. Specifically, the expressions of ACACA, FASN, DGAT2, GPAM, SCD, ELOVL6, HSD17B12, TECR, PKM, TKT, PCK1, CD44, and THBS2S genes were significantly upregulated in Mth-18 and Mth-30 compared to that in Mth-6. These genes promoted fatty acid synthesis, triglyceride synthesis, gluconeogenesis, and extracellular matrix–receptor interaction and decreased glycolysis, leading to increased adipocyte proliferation and fat deposition. Notably, our findings suggested that the reduced activity of the AMPK signaling pathway may be regulated by CAMKK2 and PP2A during sheep growth. Furthermore, our results revealed several DE miRNAs, mml-miR-320b, chi-miR-1388-3p, bta-miR-6715, oar-miR-143, and miR-424, that potentially influence fat metabolism. Overall, this study provides a theoretical basis and new insights into the molecular mechanisms of adipose tissue metabolism during growth in naturally grazing sheep. Full article

Worldwide, lung cancer is the most common cause of cancer-related death, which is made worse by the development of drug resistance during treatment. It is urgent to develop new therapeutic methods and small molecule drugs for tumor resistance. Chaetocin, extracted from Chaetomium minutum, is a natural compound with good antitumor activity. However, there are few studies on its tumor resistance. In this paper, firstly, chaetotocin significantly inhibited the viability and migration of cisplatin-resistant non-small cell lung cancer (NSCLC) cells and inhibited the xenograft growth of nude mice. Chaetocin at 4 mg/kg significantly inhibited A549/DDP xenograft growth with an inhibition rate of 70.43%. Subsequently, the underlying mechanism behind the actions of chaetocin was explored. It was discovered that chaetocin can inhibit transketolase (TKT), thereby inhibiting the growth of NSCLC cells and inducing cell death. Compared with cisplatin-sensitive cells, a lower concentration of chaetocin can inhibit cisplatin-resistance cell viability and migration. Mechanistically, TKT was identified as a potential target for chaetocin. The KD value of the interaction between chaetocin and TKT was 63.2 μM. An amount of 0.2 μM chaetocin may suppress the enzyme activity and expression level of TKT. We found the TKT expression is higher in cisplatin-resistant cells, which further explains why these cells were more vulnerable to chaetocin in terms of cell phenotype. Additionally, the muti-omics analysis and RNA interference suggested that chaetocin can inhibit the PI3K/Akt signaling pathway through TKT. In conclusion, chaetocin could directly bind to TKT, inhibiting its enzyme activity and expression, which interfered with intracellular metabolism and oxidation-reduction balance, and then regulated the PI3K/Akt signaling pathway to inhibit the growth of NSCLC and induce apoptosis. Full article

Manually crafted features often suffer from being subjective, having an inadequate accuracy, or lacking in robustness in recognition. Meanwhile, existing deep learning methods often overlook the structural and dynamic characteristics of the human hand, failing to fully explore the contextual information of joints in both the spatial and temporal domains. To effectively capture dependencies between the hand joints that are not adjacent but may have potential connections, it is essential to learn long-term relationships. This study proposes a skeleton-based hand gesture recognition framework, the ST-KT, a spatio-temporal graph convolution network, and a transformer with the Kolmogorov–Arnold Network (KAN) model. It incorporates spatio-temporal graph convolution network (ST-GCN) modules and a spatio-temporal transformer module with KAN (KAN–Transformer). ST-GCN modules, which include a spatial graph convolution network (SGCN) and a temporal convolution network (TCN), extract primary features from skeleton sequences by leveraging the strength of graph convolutional networks in the spatio-temporal domain. A spatio-temporal position embedding method integrates node features, enriching representations by including node identities and temporal information. The transformer layer includes a spatial KAN–Transformer (S-KT) and a temporal KAN–Transformer (T-KT), which further extract joint features by learning edge weights and node embeddings, providing richer feature representations and the capability for nonlinear modeling. We evaluated the performance of our method on two challenging skeleton-based dynamic gesture datasets: our method achieved an accuracy of 97.5% on the SHREC’17 track dataset and 94.3% on the DHG-14/28 dataset. These results demonstrate that our proposed method, ST-KT, effectively captures dynamic skeleton changes and complex joint relationships. Full article

Background: Saline–alkali stress is a major factor limiting the growth of oats. Sugar is the primary carbon and energy source in plants which regulates plant development and growth by regulating enzyme activity and gene expression. Sucrose, glucose, and fructose are ubiquitous plant-soluble sugars that act as signalling molecules in the transcriptional regulation of various metabolic and defence-related genes. Methods: In this study, soluble sugars, fructose, sucrose, and starch contents were measured, and transcriptomics was used to determine the differentially expressed genes (DEGs) in saline-sensitive and saline-tolerant oats after 6, 12, 24, and 48 h. DEGs annotated to carbohydrates were selected using the Kyoto Encyclopedia of Genes and Genomes. Results: DEGs involved in carbohydrate metabolism were mainly enriched in the glycolysis/gluconeogenesis and pentose phosphate pathways, fructose and mannose metabolism, and starch and sucrose metabolism. GAPDH, SUPI, SUS2, ATP-PEK, HXK6, FBA4, TBA4, TKT, ISA3, PPDK1, and BAM2 were significantly expressed, and a quantitative reverse transcription polymerase chain reaction verified the transcriptome sequencing results. Conclusions: In this study, oats with different salinity tolerances were used to determine sugar contents under four salinity stress durations, and transcriptome sequencing was used to explore the regulatory mechanism of sugars and provide a reference for elucidating the sugar signalling regulatory mechanism under abiotic stress. Full article

In Escherichia coli cells, the main enzymes involved in pentose interconversion are ribose-5-phosphate isomerases RpiA and RpiB and ribulose-5-phosphate epimerase Rpe. The inactivation of rpiAB limits ribose-5-phosphate (R5P) synthesis via the oxidative branch of the pentose phosphate pathway (PPP) and unexpectedly results in antibiotic supersensitivity. This type of metabolism is accompanied by significant changes in the level of reducing equivalents of NADPH and glutathione, as well as a sharp drop in the ATP pool. However, this redox and energy imbalance does not lead to the activation of the soxRS oxidative stress defense system but the increased sensitivity to oxidants paraquat and H₂O₂. The deletion of rpiAB leads to a significant increase in the activity of transketalase (Tkt), a key enzyme of the nonoxidative branch of the PPP and increased sensitivity to ribose added in the growth medium. The phenotype of supersensitivity of rpiAB to antibiotics and ribose can be suppressed by activating the utilization of sedoheptulose-7-phosphate, which originates from R5P, to LPS synthesis or limitation of nucleoside catabolism by the inactivation of the DeoB enzyme, responsible for conversion of ribose-1-phospate to R5P. Our results indicate that the induction of unidirectional synthesis of R5P is the cause of supersensitivity to antibiotics in rpiAB mutant. Full article

Oxidative stress has been identified as a major factor in the development and progression of pain and psychiatric disorders, but the underlying biomarkers and molecular signaling pathways remain unclear. This study aims to identify oxidative stress-related biomarkers and signaling pathways in pain–depression comorbidity. Integrated bioinformatics analyses were applied to identify key genes by comparing pain–depression comorbidity-related genes and oxidative stress-related genes. A total of 580 differentially expressed genes and 35 differentially expressed oxidative stress-related genes (DEOSGs) were identified. By using a weighted gene co-expression network analysis and a protein–protein interaction network, 43 key genes and 5 hub genes were screened out, respectively. DEOSGs were enriched in biological processes and signaling pathways related to oxidative stress and inflammation. The five hub genes, RNF24, MGAM, FOS, and TKT, were deemed potential diagnostic and prognostic markers for patients with pain–depression comorbidity. These genes may serve as valuable targets for further research and may aid in the development of early diagnosis, prevention strategies, and pharmacotherapy tools for this particular patient population. Full article

Metronidazole (MTZ) is the most common drug used against Trichomonas vaginalis (T. vaginalis) infections; however, treatment failures and high rates of recurrence of trichomoniasis have been reported, suggesting the presence of resistance in T. vaginalis to MTZ. Therefore, research into new therapeutic options against T. vaginalis infections has become increasingly urgent. This study investigated the trichomonacidal activity of a series of five imidazole carbamate compounds (AGR-1, AGR-2, AGR-3, AGR-4, and AGR-5) through in vitro susceptibility assays to determine the IC₅₀ value of each compound. All five compounds demonstrated potent trichomonacidal activity, with IC₅₀ values in the nanomolar range and AGR-2 being the most potent (IC₅₀ 400 nM). To gain insight into molecular events related to AGR-induced cell death in T. vaginalis, we analyzed the expression profiles of some metabolic genes in the trophozoites exposed to AGR compounds and MTZ. It was found that both AGR and MTZ compounds reduced the expression of the glycolytic genes (CK, PFK, TPI, and ENOL) and genes involved in metabolism (G6PD, TKT, TALDO, NADHOX, ACT, and TUB), suggesting that disturbing these key metabolic genes alters the survival of the T. vaginalis parasite and that they probably share a similar mechanism of action. Additionally, the compounds showed low cytotoxicity in the Caco-2 and HT29 cell lines, and the results of the ADMET analysis indicated that these compounds have pharmacokinetic properties similar to those of MTZ. The findings offer significant insights that can serve as a basis for future in vivo studies of the compounds as a potential new treatment against T. vaginalis. Full article

Dongbei Suaicai (DBSC) has a complicated microbial ecosystem in which the composition and metabolism of microbial communities during the process have not been well explored. Here, combined metagenomic and metaproteomic technology was used to reveal the taxonomic and metabolic profiles of DBSC. The results showed that firmicutes and proteobacteria were the prevalent bacteria in phylum and Pseudomonas, while Weissella, Pediococcus, and Leuconostoc were the prevalent genus. The vital metabolic pathways were involved in glycolysis/gluconeogenesis [path: ko00010], as well as pyruvate metabolism [path: ko00620], fructose and mannose metabolism [path: Ko00051], glycine, and serine and threonine metabolism [path: Ko00260]. Moreover, the key proteins (dps, fliC, tsf, fusA, atpD, metQ, pgi, tpiA, eno, alaS, bglA, tktA, gor, pdhD, aceE, and gnd) in related metabolized pathways were enriched during fermentation. This study will aid in facilitating the understanding of the fermentation mechanisms of DBSC. Full article

Electronic tickets (e-tickets) are gradually being adopted as a substitute for paper-based tickets to bring convenience to customers, corporations, and governments. However, their adoption faces a number of practical challenges, such as flexibility, privacy, secure storage, and inability to deploy on IoT devices such as smartphones. These concerns motivate the current research on e-ticket systems, which seeks to ensure the unforgeability and authenticity of e-tickets while simultaneously protecting user privacy. Many existing schemes cannot fully satisfy all these requirements. To improve on the current state-of-the-art solutions, this paper constructs a blockchain-enhanced privacy-preserving e-ticket system for IoT devices, dubbed PriTKT, which is based on blockchain, structure-preserving signatures (SPS), unlinkable redactable signatures (URS), and zero-knowledge proofs (ZKP). It supports flexible policy-based ticket purchasing and ensures user unlinkability. According to the data minimization and revealing principle of GDPR, PriTKT empowers users to selectively disclose subsets of (necessary) attributes to sellers as long as the disclosed attributes satisfy ticket purchasing policies. In addition, benefiting from the decentralization and immutability of blockchain, effective detection and efficient tracing of double spending of e-tickets are supported in PriTKT. Considering the impracticality of existing e-tickets schemes with burdensome ZKPs, we replace them with URS/SPS or efficient ZKP to significantly improve the efficiency of ticket issuing and make it suitable for use on smartphones. Full article

Transketolase (TKT) is an essential thiamine diphosphate (ThDP)-dependent enzyme of the non-oxidative branch of the pentose phosphate pathway, with the glucose-6P flux through the pathway regulated in various medically important conditions. Here, we characterize the brain TKT regulation by acylation in rats with perturbed thiamine-dependent metabolism, known to occur in neurodegenerative diseases. The perturbations are modeled by the administration of oxythiamine inhibiting ThDP-dependent enzymes in vivo or by reduced thiamine availability in the presence of metformin and amprolium, inhibiting intracellular thiamine transporters. Compared to control rats, chronic administration of oxythiamine does not significantly change the modification level of the two detected TKT acetylation sites (K6 and K102) but doubles malonylation of TKT K499, concomitantly decreasing 1.7-fold the level of demalonylase sirtuin 5. The inhibitors of thiamine transporters do not change average levels of TKT acylation or sirtuin 5. TKT structures indicate that the acylated residues are distant from the active sites. The acylations-perturbed electrostatic interactions may be involved in conformational shifts and/or the formation of TKT complexes with other proteins or nucleic acids. Acetylation of K102 may affect the active site entrance/exit and subunit interactions. Correlation analysis reveals that the action of oxythiamine is characterized by significant negative correlations of K499 malonylation or K6 acetylation with TKT activity, not observed upon the action of the inhibitors of thiamine transport. However, the transport inhibitors induce significant negative correlations between the TKT activity and K102 acetylation or TKT expression, absent in the oxythiamine group. Thus, perturbations in the ThDP-dependent catalysis or thiamine transport manifest in the insult-specific patterns of the brain TKT malonylation and acetylations. Full article

Golden mahseer (Tor putitora) is a critically endangered fish with significant economic importance. However, its reproductive challenges in a captive environment pose a limitation to the successful domestication and aquaculture potential of this species. To understand the role of various genes in gonad maturation and reproduction in golden mahseer, we conducted an RNA-sequencing (RNA-Seq) study on the brains of mature male and female specimens. Altogether, 20.6 and 21.5 million reads were generated from the brains of the male and female fish, respectively. A total of 26,989 and 55,600 cDNA coding sequences (CDS) were identified from the male and female brains, respectively, among which 26,258 CDS from the male brain and 53,446 CDS from the female brain demonstrated homology to known protein database sequences. A comprehensive analysis revealed a total of 1187 distinct differentially expressed upregulated genes (DEGs), encompassing 953 DEGs anticipated to exhibit upregulation in the female brain and 234 DEGs in the male brain. Furthermore, in the brain of female and male golden mahseer, a significant downregulation was observed in 492 and 744 genes, respectively, resulting in a cumulative count of 1236 downregulated genes. Validation of the RNA-Seq results was performed by quantitative real-time PCR (qPCR) using 24 genes. Sixteen candidate genes with differential expression levels between the male and female fish were then selected and analyzed via qPCR. The results confirmed that amh, foxl3, dax1, kif20, and tkt were upregulated in the male golden mahseer brain, while cyp19a1a, dmrt2a, gdf9, sox9b, wt-1a, and aqp1 were upregulated in the female golden mahseer brain. Our study elucidates the distinct gene expression profiles in male and female golden mahseer brains and thus offers valuable insights for potential reproductive manipulation strategies in this fish species. Full article

This study looked at genetic polymorphisms and transcript levels of immune, antioxidant, and erythritol-related markers for postparturient endometritis prediction and tracking in Holstein dairy cows. One hundred and thirty female dairy cows (65 endometritis affected and 65 apparently healthy) were used. Nucleotide sequence variations between healthy and endometritis-affected cows were revealed using PCR-DNA sequencing for immune (TLR4, TLR7, TNF-α, IL10, NCF4, and LITAF), antioxidant (ATOX1, GST, and OXSR1), and erythritol-related (TKT, RPIA, and AMPD1) genes. Chi-square investigation exposed a noteworthy variance amongst cow groups with and without endometritis in likelihood of dispersal of all distinguished nucleotide variants (p < 0.05). The IL10, ATOX1, and GST genes were expressed at substantially lower levels in endometritis-affected cows. Gene expression levels were considerably higher in endometritis-affected cows than in resistant ones for the genes TLR4, TLR7, TNF-α, NCF4, LITAF, OXSR1, TKT, RPIA, and AMPD1. The sort of marker and vulnerability or resistance to endometritis had a significant impact on the transcript levels of the studied indicators. The outcomes might confirm the importance of nucleotide variants along with gene expression patterns as markers of postparturient endometritis susceptibility/resistance and provide a workable control plan for Holstein dairy cows. Full article

The nasal microenvironment plays a crucial role in the transmission, modulation, and clinical progression of COVID-19; however, the immune responses at the site of viral entry remain poorly understood. We deciphered the link between nasopharyngeal (NP) immune and inflammatory response that triggers cytokine/chemokine storms in the nasal route of COVID-19-positive patients. We used RT-PCR, multiplex ELISA, flow cytometry, and LC-MS/MS to decipher nasopharyngeal immune perturbations associated with severe COVID-19. In addition, we performed in vitro assays using cultured human monocytes-derived macrophages trained both in the presence and absence of SARS-CoV-2 trimeric spike protein(s) and co-cultured with and without autologous human peripheral blood mononuclear cells (hPBMCs)/total T-cells/CD8 T-cells. In vitro immune perturbations were examined by flow cytometry and LC-MS/MS assays. Our findings confirm that macrophages orchestrate NP immune inflammatory responses and highlight the cytokine/chemokine storms associated with the increased CD8${}^{+}$T-cells along with Tregs, Th1, and Th17.1 T-helper cells. We observed a correlation between in vitro and nasal findings that trained macrophages, profoundly M2c, differentially promote the inflammatory surfactome on CD8 T-cells, including ITGAM, LGALS3, CD38, TKT, LRPAP1, and SSBP1. The findings of this study conclude that inflammatory lymphocyte perturbations within the nasopharynx of COVID-19 patients may enforce immune homeostasis during SARS-CoV-2-infection and contribute to COVID-19 pathology. This study explored the therapeutic target proteins that could facilitate the development of new medications, which could allow for immediate treatment of possible emerging viral infections. Full article

A new concept of a space-based synchronized reference network is proposed with the development of an optical frequency reference and laser inter-satellite link. To build such time reference, three clock ensemble algorithms, namely the natural Kalman timescale (NKT) algorithm, the reduced Kalman timescale (RKT) algorithm, and the two-stage Kalman timescale (TKT) algorithm are considered. This study analyzes and compares the performance of these algorithms using BDS, GPS, and Galileo satellite clock data from the GFZ GNSS clock corrections, which will be used in constructing future space-based time references. The study shows that the NKT algorithm improves frequency stability by 0.1–0.2 orders of magnitude in the short and medium term. When the satellite clock is mostly a hydrogen clock, the RKT and NKT are close, and the short and medium-term frequency stability slightly increases. In contrast, the TKT algorithm produces a timescale that improves frequency stability by 1–3 orders of magnitude. A quadratic polynomial model predicts the three timescales, with the results indicating that the short-term prediction accuracy of the satellite clock is within 1ns, and the TKT algorithm’s prediction accuracy is 1–2 orders of magnitude higher than that of the NKT and RKT algorithms. With the deployment of next-generation Low Earth Orbit (LEO) satellites equipped with higher-precision clocks, the space-based time reference system will achieve improved accuracy and greater potential for practical applications. Full article